1-{8 {65 -O-Amino-p-halophenyl-oxy, thio or sulfinyl)-propyl{9 -4-(alkoxy or halo phenyl)piperazines

ABSTRACT

WHEREIN Y is as defined above.   WHEREIN R1, R2, R3, Z and m are as defined above and X is halogen atom, with a compound of the formula,   (WHEREIN R4 is hydrogen or halogen atom or lower alkyl or lower alkoxy group; R5 is hydrogen atom or lower alkyl or lower alkanoyl group; R6 is hydrogen or halogen atom or lower alkyl or lower alkoxy group; R7 is hydroxy, lower alkoxy or lower alkanoyloxy group; R8 is hydrogen or halogen atom or lower alkyl, lower alkoxy or trifluoromethyl group; R9 is hydrogen atom or lower alkyl or lower alkanoyl group; R10 is hydrogen or halogen atom or lower alkyl or lower alkoxy group; and n is 0, 1 or 2); and m is an integer from 2 to 5, and pharmaceutically acceptable salts thereof, which have excellent anti-psychotonic, analgesic, anti-inflammatory and anti-hypertensive activities, are produced by reacting a compound of the formula,   WHEREIN R1 and R2 are each hydrogen atom or lower alkyl, lower alkanoyl or aroyl group; R3 is hydrogen or halogen atom or lower alkyl or lower alkoxy group; Z is oxygen or sulfur atom or sulfinyl or sulfonyl group; Y is   Novel alkylamine derivatives represented by the formula,

United States Patent 1191 Maruyama et al.

l l l-[y-O-AMlNO-P-HALOPHENY L-OXY, THIO OR SULFINYL)-PROPYL]-4-(ALKOXY OR HALO PHENYLlPlPERAZlNES [75] Inventors: lsamu Maruyama, Minoo; Masaru Nakao; Kikuo Sasajima, both of Toyonaka; Keiichi Ono, Osaka; Masaharu Takayama, Minoo; Shigenari Katayama; Yoshihiro Tanaka, both of Takarazuka; lzumi Yanagihara, Osaka; Shigeho lnaba, Takarazuka; Hisao Yamamoto, Nishinomiya, all of Japan [73} Assignee: Sumitomo Chemical Company, Ltd.,

Osaka, Japan 22 Filed: Dec. 4, 1972 211 Appl. No; 312,106

[30] Foreign Application Priority Data Dec, 3, l97l Japan 1687939 [56] References Cited UNITED STATES PATENTS 3,270,004 8/l966 Alter 260/239 3,577,422 5/l97l Wideburg et al. 260/268 PH FOREIGN PATENTS OR APPLICATIONS 984,0l7 2/l965 United Kingdom 1,053,30l l2/l966 United Kingdom Primary ExaminerRichard J. Gallagher Assistant ExaminerJose Tovar Attorney, Agent, or FirmStevens, Davis, Miller & Mosher ABSTRACT Novel alkylamine derivatives represented by the formula,

Q 2 C ll2 N Y Dec. 9, 1975 (wherein R is hydrogen or halogen atom or lower alkyl or lower alkoxy group; R is hydrogen atom or lower alkyl or lower alkanoyl group; R, is hydrogen or halogen atom or lower alkyl or lower alkoxy group; R is hydroxy, lower alkoxy or lower alkanoyloxy group; R is hydrogen or halogen atom or lower alkyl, lower alkoxy or trifluoromethyl group; R is hydrogen atom or lower alkyl or lower alkanoyl group; R is hydrogen or halogen atom or lower alkyl or lower alkoxy group; and n is 0, 1 or 2); and m is an integer from 2 to 5, and pharmaceutically acceptable salts thereof, which have excellent anti-psychotonic, analgesic, antiinflammatory and anti-hypertensive activities, are produced by reacting a compound of the formula,

wherein R,, R R-,, Z and m are as defined above and X is halogen atom, with a compound of the formula,

(III) 6 Claims, No Drawings l-[Y-O-AMlNO-P-HALOPHENYL-OXY, THIO OR SULFlNYL)-PROPYL]-4-(ALKOXY OR HALO PHENYL)PIPERAZINES The present invention relates to novel alkylamine derrvatives and pharmaceutically acceptable salts thereof and preparation thereof. More particularly, the present invention pertains to novel alkylamine derivatives represented by the formula,

wherein R and R are each hydrogen atom or lower alkyl, lower alkanoyl or aroyl group; R is hydrogen or halogen atom or lower alkyl or lower alkoxy group; Z is oxygen or sulfur atom or sulfinyl or sulfonyl group; Y is (wherein R is hydrogen or halogen atom or lower alkyl group or lower alkoxy group; R is hydrogen atom or lower alkyl or lower alkanoyl group; R, is hydrogen or halogen atom or lower alkyl or lower alkoxy group; R is hydroxy, lower alkoxy or lower alkanoyloxy group; R is hydrogen or halogen atom or lower alkyl, lower alkoxy or trifluoromethyl group; R, is hydrogen atom or lower alkyl or lower alkanoyl group; R is hydrogen or halogen atom or lower alkyl or lower alkoxy group; and n is 0, l or 2); and m is an integer from 2 to 5, and

pharmaceutically acceptable salts thereof, and to a process for preparation of the same.

As used herein, the term lower alkyl," lower alkoxy and lower alkanoyl means such groups containing from one to seven carbon atoms which can be either straight or branched, and thus the lower-alkyl moiety represents, for example, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-hexyl and the like, and loweralkanoyl represents, for example, formyl, acetyl, propionyl, butyryl and the like. The term halogen" includes all four halogens, i.e., iodine, bromine, chlorine and fluorine. The term aroyl" means benzoyl, lower alkylor halogen-substituted benzoyl, naphthoyl, thenoyl or nicotinoyl and the like. The group of the formula C,,.H represents a stragiht chain or branched chain alkylene group, for example, ethylene, trimethylene, tetramethylene, methyltrimethylene, ethyltrimethylene, methyltetramethylene and the like.

The alkylamine derivatives of this invention can form pharmaceutically acceptable salts with a variety of organic and inorganic acids, such as oxalic, citric, lactic, maleic, malic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic, ascorbic, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic and sulfamic acids.

The compounds of the formula (I) and their acid addition salts are novel and have valuable pharmacological properties, such as excellent anti-psychotonic, analgesic, antiinflammatory or anti-hypertensive activities.

Each of the pharmaceutically active compounds of this invention may be, e.g., incorporated, for oral administration, in a tablet as the sole active ingredient. A typical tablet is constituted from 1 to 20 percent binder, e.g. tragacanth; from I to 20 percent lubricant, e.g. talcum, magnesium stearate, etc.; an average dose of active ingredient; and q.s. percent of filler, e.g. lactose. The usual oral dosage is l to 1000 mg per os daily.

Accordingly, an object of the present invention is to provide novel and useful alkylamine derivatives and salts thereof which have excellent pharmacological properties. Another object is to provide a process for producing such novel and useful alkylamine derivatives and salts thereof. A further object is to provide a pharmaceutical composition containing such novel and useful alkylamine derivatives or salts thereof. Other objects and merits of the present invention will be apparent from the following descriptions.

According to the present invention, the novel alkylamine derivatives represented by the formula (I) are prepared by a method which comprises reacting a compound represented by the formula,

wherein R,, R R Z and m are as defined above and X is halogen atom, with a compound represented by the formula,

(III) wherein Y is as defined above. The halogen atoms represented by X in the above-mentioned formula (II) include chlorine, bromine and iodine atoms.

The reaction may be carried out in the absence or presence of an acid acceptor, the purpose of which is to take up the hydrogen halide split off during the course of the reaction. Suitable acid acceptors include sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, triethylamine and the like. The reaction may be carried out in the presence of a solvent or solvent mixture. Suitable solvents include benzene, toluene, xylene, dimethylformamide, pyridine, methanol, ethanol and the like, and a mixture thereof. The reaction may be carried out at a temperature within a range between about room temperature and the boiling point of the solvent employed. The thus obtained alkylamine derivatives of the formula (1) in free base form are converted to the acidaddition salt form by the conventional procedure.

According to the above process, there are obtained, for example, the following alkylamine derivatives.

l-Phenyl-8-[-y-(2'-acetylamino-4 -fluorophenoxy)- propyl1-4-oxo-l ,3,8-triazaspiro[4,5 ]decane l-Phenyl-8-[ -y-( 2 '-acetylamino-4 '-methoxyphenoxy)-propyl]-4-oxol ,3 ,8-triazaspiro[4,5 ]decane l-Phenyl-8-[-y-(2'-acetylamino-4'-methylphenoxy)- propyl1-4-oxol ,3 ,8-triazaspiro[4,5 ]decane l-['y-(2' Acetylamino4'-fluorophenoxy)propyl1-4- (2-oxo- 1 -benzimidazolynyl )piperidine l-['y-(2'-Amino-4'-fluorophenoxy)propyl]-4-(2-oxol-benzimidazolynyl)piperidine l-[-y-(2'-Acetylamino-4'-fluorophenoxy)propyl1-4- (p-chlorophenyl)-4-hydroxypiperidine 1-[ -(2'-Acetylamino-4-t'luorophenoxy)propyl1-4- (o-methoxyphenyl)piperazine l-[7-(2'-Acetylamino-4'-fluorophenylthio)propyl]- 4-(o-methoxyphenyl)piperazine I -[y-( 2 '-Acetylamino-4 -fluorophenylthio )propyl]- 4-(p-chlorophenyl)-4-hydroxypiperidine l-[y-( 2'-Acetylamino-4 '-fluorophenylthio)propyll- 4-hydroxy-4-(m-trifluoromethylphenyl)piperidine l-[ 2'-Acetylamino-4'-fluorophenylthio)propyl]- 4-p-tolyl-4-hydroxypiperidine l-['y-(2-Acetylamino-4'-fluorophenylthio)propyl]- 4-(p-chlorophenyl)-4-(acetyloxy)piperidine 4-( 2-oxol -benzim idazolynyl )piperidine l-[y-( 2'-Acetylamino-4 '-fluorophenylthio )propyll- 4-(3-acetyl-2-oxo-l-benzimidazolynyl)piperidine 1-Phenyl-8-['y-(2'-acetylamino-4'-fluorophenylthio)- propyl1-4-oxol ,3 ,8-triazaspiro[4,5 ]decane l -Phenyl-8-[7-(2'-benzoylamino-4'-fluorophenylthio )-propyl}-4-oxo-l ,3,8-triazaspiro[4,5 ]decane l-Phenyl-3acetyl-8-[y-( 2' acetylamino-4-fluorophenylthio)propyl -4-oxol ,3 ,8-triazaspiro- [4,51decane 1-Phenyl-3 -methyl-8-['y-( 2 '-acetylamino-4 '-fluorophenylthio)propyl1-4-oxo-l ,3 ,S-triazaspiro- [4,51decane l-Phenyl-8-[-y-(2'-N-acetylmethylamino-4'-fluorophenylthio)propyl]-4-oxo-l ,3,8-triazaspiro- [4,51decane l-Phenyl-8-[y-(2-methylamino-4'-fluorophenylthio)-propyl]-4-oxol ,3 ,8-triazaspiro[4,5 ]decane l-[y-(2'-Acetylamino-4 '-fluorophenylsulfinyl propyl1-4-(o-methoxyphenyl)piperazine 4 l-['y-(2'-Amino-4'-fluorophenylsulfinyl)propyll-4- (o-methoxyphenyl)piperazine 1-['y-(2'-Propionylamino-4'-fluorophenylsulfinyl)- propyl l-4-(o methoxyphenyl)piperazine l-[y-( 2 -Acetylamino-4'-fluorophenylsulfinyl propyl1-4-(p-chlorophenyl)-4-hydroxypiperidine l-[y-( 2 '-Acetylamino-4'-fluorophenylsulfinyl propyl -4-( 2-oxol -benzimidazolynyl)piperidine l-Phenyl-8-l'y-(2'-acetylamino-4'-fluorophenylsulfinyl)-propyl ]-4-oxo-l ,3 ,8-triazaspiro[4,5 ]decane I-['y-(2'-Acetylamino-4'-fluorophenylsulfonyl)- propyl]-4-(o-methoxyphenyl)piperazine l-['y(2'-Acetylamino-4'-fluorophenylsulfonyl)- propyl]-4-(p-chlorophenyl)-4-hydroxypiperidine l-['y-( 2'-Acetylamino-4'-fluorophenylsulfonyl propyl]-4-( 2-oxo-l -benzimidazolynyl )piperidine l-Phenyl-8-[7-(2 '-acetylamino-4'-fluorophenylsulfonyl )propyl1-4-oxo-l ,3,8-triazaspiro-[4,5 ]decane This invention is further disclosed in the following examples of more preferred embodiments thereof, which are presented for the purpose of illustration and it is not intended to limit the scope of the invention.

. EXAMPLE I A mixture of 1.97 g of 2-(-y-chloropropoxy)-5'- fluoroacetanilide, 1.54 g of l-(o-methoxyphenyl)-piperazine, 0.43 g of sodium carbonate and 30 ml of dimethylformamide was heated for 6 hours at a temperature of 90C. After cooling, the reaction mixture was poured into ml of water and an oily material was extracted with benzene. The organic layer was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The oily residue was dissolved in ether and treated with ethanolic hydrogen chloride with cooling. The precipitate was collected by filtration and dried to give 1-[-y-(2'-acetylamino-4'- fluorophenoxy)-propyl]-4-(o-methoxyphenyl)piperazine hydrochloride, m.p. 234-5C (decomp.). Recrystallization from ethanol gave white crystals, m.p. 235-7C (decomp.).

The following compounds were obtained in accordance with the manner similar to that of Example 1:

methoxyphenyl)piperazine, m.p. l08.5-l 10C.

l ['y-( 2-Acetylamino-4-fluorophenoxy )propyll-4 (o-chlorophenyl )piperazine oxalate, m .p.

chlorophenyhpiperazine dihydrochloride, m.p.

255-6C 1-['y-(2'Aminophenylthio)propyll-4-phenylpiperazine trihydrochloride, m.p. 247-9C (decomp.)

l-[y-( 2 '-Acetylamino-4-fluorophenylthio)propyl]- 4-(o-methoxyphenyl)piperazine dihydrochloride, m.p. l75-l80C (decomp.)

l-[y-(2 '-Amino-4'-fluorophenylthio )propyl1-4-(omethoxyphenyl)piperazine hydrochloride, m.p. 2l3-5C (decomp.)

l-[y-( 2 -Acetylamino-4'-fluorophenylsulfinyl)- propyl]-4-(o-methoxyphenyl)piperazine oxalate, m.p. l256C (decomp.)

I-['y-(2'-Acetylamino-4'-chlorophenoxy)propyl1-4- (Z-oxo-1-benzimidazolinyl)piperidine, m.p. lll-6C (decomp.)

l-[-y-( 2 '-Amino-4-chlorophenoxy)propyl]-4-( 2- oxo- 1-benzimidazolinyl)piperidine dihydrochloride, m.p. 2l5220C (decomp.) 

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1, wherein Z is sulfur.
 3. 1-( gamma -(2''Acetylamino-4''-fluorophenylthio)propyl)-4-(o-methoxyphenyl)piperazine dihydrochloride.
 4. 1-( gamma -(2''-Acetylamino-4''-fluorophenoxy)-propyl)-4-(o-methoxyphenyl)piperazine hydrochloride.
 5. 1-( gamma -(2''-Amino-4''-fluorophenoxy)propyl)-4-(o-methoxyphenyl)piperazine.
 6. 1-( gamma -(2''-Acetylamino-4''-fluorophenyl-sulfinyl)propyl)-4-(o -methoxyphenyl)piperazine oxalate. 